Breast cancer is one of the most commonly diagnosed cancers in women, and the disease affects many women's lives every day. Since the final stage of the disease is very difficult to cure, we need to consider different approaches to overcome this disease, such as prevention at an early stage. Preventive approaches, as shown by the successful clinical trials of selective estrogen receptor modulators (SERMs) for the prevention of estrogen receptor (ER) positive breast cancer, have contributed to improvement in the management of this disease. However, the benefit of these SERMs in the treatment of breast cancer is still far from a total cure, in particular with ER negative breast cancer. We have been interested in developing new agents based on their mechanisms of action, and we propose studying a nuclear receptor and its ligands for chemoprevention of breast cancer. The vitamin D receptor (VDR) is a member of the nuclear receptor family, and its ligands have been implicated in the regulation of many biological processes including cell growth, differentiation, and apoptosis in the breast, colon, prostate, and other organs. Although the ability of vitamin D analogs to arrest growth in many cancer cell types has been reported, the effects and the mechanisms of action of vitamin D derivatives in ER negative breast cancer remains to be investigated. Unique features of this proposal are studies with novel vitamin D analogs with decreased toxicity that have effects independent of estrogen receptor, and the utilization of the human MCF10 progressive breast cancer model that resembles and covers the different spectrum of breast carcinogenesis. We will determine the ability of novel vitamin D analogs to prevent breast cancer in an in vivo xenograft model using nude mice, and further investigate the role of the vitamin D analogs on the regulation of transforming growth factor-( (TGF-()/Smad signaling in these cells. The goal of this proposal is to develop novel ligands for the vitamin D receptor as potential chemopreventive agents that can ultimately be used to prevent breast cancer.